Approximately 50 million people world-wide are blind and approximately 150 million are significantly vision impaired. Except for trauma and infections, the majority of human eye diseases are genetic in nature. The number of human loci causing retinal disease is approximately 9-fold greater than the number of available associated animal models, indicating a large gap in models for studying diseases that are known to occur in humans. The mouse with its well-developed genetics, similarity to human physiology and anatomy, and accessibility for genetic manipulation is a widely accepted and useful model system. Mouse models have been used to provide candidate genes for human diseases, tissues for study throughout development and disease progression, and test systems for therapies. They are also an ideal platform to identify and dissect biologically relevant pathways through genetic means. While there are many strategies available to generate mouse models, chemical mutagenesis is one of the most efficient methods to produce mice with eye diseases. ENU-induced mutations allow unbiased identification of a wide array of genes with different effects on ocular biology. In the present application, we will screen approximately 10,000 aged G3 mice by indirect ophthalmoscopy, slit lamp biomicroscopy, and electroretinography. Our goal is to identify 50 models with heritable anterior segment or posterior segment abnormalities. Importantly, of these, we will map or complementation test approximately 30 models with retinal abnormalities and go on to positionally candidate test or clone 10-20 of these using a combination of standard and assisted reproductive approaches. Mice with proven heritable mutations will be made available to the vision research community through a website established in this grant and through the well-developed JAX distribution system for mice generated from research colonies. Anterior segment or fundus photo-documentation, electroretinography and histology will be provided for all models at two appropriate ages to determine if the disease is stationary or progressive. In the retinal models where the underlying molecular basis is determined, a developmental expression profile will be established by real time PCR, and in situ analysis of the eye will be carried out at an age in which expression is highest. Successful conclusion of this proposal will not only generate well characterized ocular models, but will potentially identify entry points into new pathways that are important in eye biology and afford us the opportunity to build and test hypotheses about normal ocular function and disease pathology.